The mechanism by which the group A streptococci bring about the non-suppurative or late sequelae such as rheumatic fever and glomerulonephritis in human hosts has not been resolved. The rationale for our research objective is based on the concept that group A streptococci produce exotoxins capable of modifying the host-response to injury; it is assumed that this type of injury is required to evoke other mechanisms involving autoimmune reactions or cell-wall complexes. We believe that the pyrogenic exotoxins closely associate with the so- called erythrogenic toxins play the most significant role in bringing about these events. There are at least three distinct antigenic types: They are low molecular weight (29,000) proteins complexed with hyaluronic acid. These toxins are immunogenic and it is possible to immunize experimental animals against their many pathophysiological effects. Of these, one of the most significant is the ability to enhance profoundly the susceptibility of rabbits, mice and monkeys to endotoxin shock. It is conceivable that this represents an important early sequelae of streptococcal infection when coincident with gram- negative bacterial infections. In rabbits this enhancement is greater than 100,000-fold. The ultimate aim is to develop a non-toxic multivalent toxoid which will protect the tissues and the host against the early and late sequelae even though group A streptococcal infection occurs. In addition, it is essential that specific antisera for each toxin be made available, and a rapid and simple method be developed for the characterization of the exotoxins produced by those group A streptococci recently associated with one or more sequelae.